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Nutrients May 2023The areca nut is often consumed as a chewing food in the Asian region. Our previous study revealed that the areca nut is rich in polyphenols with high antioxidant...
The areca nut is often consumed as a chewing food in the Asian region. Our previous study revealed that the areca nut is rich in polyphenols with high antioxidant activity. In this study, we further assessed the effects and molecular mechanisms of the areca nut and its major ingredients on a Western diet-induced mice dyslipidemia model. Male C57BL/6N mice were divided into five groups and fed with a normal diet (ND), Western diet (WD), WD with areca nut extracts (ANE), areca nut polyphenols (ANP), and arecoline (ARE) for 12 weeks. The results revealed that ANP significantly reduced WD-induced body weight, liver weight, epididymal fat, and liver total lipid. Serum biomarkers showed that ANP ameliorated WD-enhanced total cholesterol and non-high-density lipoprotein (non-HDL). Moreover, analysis of cellular signaling pathways revealed that sterol regulatory element-binding protein 2 (SREBP2) and enzyme 3-hydroxy-3-methylglutaryld coenzyme A reductase (HMGCR) were significantly downregulated by ANP. The results of gut microbiota analysis revealed that ANP increased the abundance of beneficial bacterium and decreased the abundance of the pathogenic bacterium while ARE shown the opposite result to ANP. In summary, our data indicated that areca nut polyphenol ameliorated WD-induced dyslipidemia by increasing the abundance of beneficial bacteria in the gut microbiota and reducing the expressions of SREBP2 and HMGCR while areca nut ARE inhibited this improvement potential.
Topics: Male; Mice; Animals; Areca; Non-alcoholic Fatty Liver Disease; Nuts; Diet, Western; Mice, Inbred C57BL; Arecoline; Plant Extracts
PubMed: 37242285
DOI: 10.3390/nu15102403 -
International Journal of Molecular... May 2023Areca nut (AN) is used for traditional herbal medicine and social activities in several countries. It was used as early as about A.D. 25-220 as a remedy. Traditionally,... (Review)
Review
Areca nut (AN) is used for traditional herbal medicine and social activities in several countries. It was used as early as about A.D. 25-220 as a remedy. Traditionally, AN was applied for several medicinal functions. However, it was also reported to have toxicological effects. In this review article, we updated recent trends of research in addition to acquire new knowledge about AN. First, the history of AN usage from ancient years was described. Then, the chemical components of AN and their biological functions was compared; arecoline is an especially important compound in AN. AN extract has different effects caused by different components. Thus, the dual effects of AN with pharmacological and toxicological effects were summarized. Finally, we described perspectives, trends and challenges of AN. It will provide the insight of removing or modifying the toxic compounds of AN extractions for enhancing their pharmacological activity to treat several diseases in future applications.
Topics: Plant Extracts; Areca; Nuts; Arecoline; Plants, Medicinal
PubMed: 37240342
DOI: 10.3390/ijms24108996 -
Ecotoxicology and Environmental Safety Jul 2023Arecoline is a critical bioactive component in areca nuts with toxicity and pharmacological activities. However, its effects on body health remain unclear. Here, we...
Arecoline is a critical bioactive component in areca nuts with toxicity and pharmacological activities. However, its effects on body health remain unclear. Here, we investigated the effects of arecoline on physiologic and biochemical parameters in mouse serum, liver, brain, and intestine. The effect of arecoline on gut microbiota was investigated based on shotgun metagenomic sequencing. The results showed that arecoline promoted lipid metabolism in mice, manifested as significantly reduced serum TC and TG and liver TC levels and a reduction in abdominal fat accumulation. Arecoline intake significantly modulated the neurotransmitters 5-HT and NE levels in the brain. Notably, arecoline intervention significantly increased serum IL-6 and LPS levels, leading to inflammation in the body. High-dose arecoline significantly reduced liver GSH levels and increased MDA levels, which led to oxidative stress in the liver. Arecoline intake promoted the release of intestinal IL-6 and IL-1β, causing intestinal injury. In addition, we observed a significant response of gut microbiota to arecoline intake, reflecting significant changes in diversity and function of the gut microbes. Further mechanistic exploration suggested that arecoline intake can regulate gut microbes and ultimately affect the host's health. This study provided technical help for the pharmacochemical application and toxicity control of arecoline.
Topics: Animals; Mice; Arecoline; Interleukin-6; Gastrointestinal Microbiome; Lipid Metabolism; Liver
PubMed: 37224782
DOI: 10.1016/j.ecoenv.2023.115055 -
Cells Apr 2023Betel quid and areca nut are complex mixture carcinogens, but little is known about whether their derived single-agent arecoline or arecoline -oxide (ANO) is...
Betel quid and areca nut are complex mixture carcinogens, but little is known about whether their derived single-agent arecoline or arecoline -oxide (ANO) is carcinogenic, and the underlying mechanisms remain unclear. In this systematic review, we analyzed recent studies on the roles of arecoline and ANO in cancer and strategies to block carcinogenesis. In the oral cavity, flavin-containing monooxygenase 3 oxidizes arecoline to ANO, and both alkaloids conjugate with -acetylcysteine to form mercapturic acid compounds, which are excreted in urine, reducing arecoline and ANO toxicity. However, detoxification may not be complete. Arecoline and ANO upregulated protein expression in oral cancer tissue from areca nut users compared to expression levels in adjacent normal tissue, suggesting a causal relationship between these compounds and oral cancer. Sublingual fibrosis, hyperplasia, and oral leukoplakia were diagnosed in mice subjected to oral mucosal smearing of ANO. ANO is more cytotoxic and genotoxic than arecoline. During carcinogenesis and metastasis, these compounds increase the expression of epithelial-mesenchymal transition (EMT) inducers such as reactive oxygen species, transforming growth factor-β1, Notch receptor-1, and inflammatory cytokines, and they activate EMT-related proteins. Arecoline-induced epigenetic markers such as sirtuin-1 hypermethylation, low protein expression of miR-22, and miR-886-3-p accelerate oral cancer progression. Antioxidants and targeted inhibitors of the EMT inducers used reduce the risk of oral cancer development and progression. Our review findings substantiate the association of arecoline and ANO with oral cancer. Both of these single compounds are likely carcinogenic to humans, and their mechanisms and pathways of carcinogenesis are useful indicators for cancer therapy and prognosis.
Topics: Arecoline; Cyclic N-Oxides; Mouth Neoplasms; Carcinogenesis; Humans; Animals; Mice; Areca; Oxygenases; Oxidation-Reduction; Acetylcysteine; Epigenesis, Genetic; Carcinogens
PubMed: 37190117
DOI: 10.3390/cells12081208 -
PeerJ 2023Cellular senescence is strongly associated with fibrosis and tumorigenesis. However, whether the epithelium of oral submucous fibrosis (OSF) undergoes premature...
OBJECTIVES
Cellular senescence is strongly associated with fibrosis and tumorigenesis. However, whether the epithelium of oral submucous fibrosis (OSF) undergoes premature senescence remains unclear. This study investigates the roles of senescent epithelial cells in OSF.
METHODS
The immunohistochemistry and Sudan black B staining were performed to identify epithelium senescence in OSF tissues. Arecoline was used to induce human oral keratinocytes (HOKs) senescence. The cell morphology, senescence-associated β galactosidase activity, cell counting Kit 8, immunofluorescence, quantitative real-time PCR, and western blot assay were used to identification of senescent HOKs. The enzyme-linked immunosorbent assay was exerted to evaluate the levels of transforming growth factor β1 (TGF-β1) in the supernatants of HOKs treated with or without arecoline.
RESULTS
The senescence-associated markers, p16 and p21, were overexpressed in OSF epithelium. These expressions were correlated with alpha-smooth actin (α-SMA) positively and proliferating cell nuclear antigen (PCNA) negatively. Moreover, Sudan black staining showed that there was more lipofuscin in OSF epithelium. In vitro, HOKs treated with arecoline showed senescence-associated characteristics including enlarged and flattened morphology, senescence-associated β galactosidase staining, cell growth arrest, γH2A.X foci, upregulation of p53, p21, and TGF-β1 protein levels. Moreover, senescent HOKs secreted more TGF-β1.
CONCLUSIONS
Senescent epithelial cells are involved in OSF progression and may become a promising target for OSF treatment.
Topics: Humans; Transforming Growth Factor beta1; Oral Submucous Fibrosis; Arecoline; Keratinocytes; beta-Galactosidase
PubMed: 37096061
DOI: 10.7717/peerj.15158 -
Journal of Acute Medicine Mar 2023This case involves a 41-year-old male experiencing agitation and confusion due to betel nut intoxication. The diagnosis was made by identifying the toxidrome through...
This case involves a 41-year-old male experiencing agitation and confusion due to betel nut intoxication. The diagnosis was made by identifying the toxidrome through physical examination. Removing the residual betel nut with a finger and brushing it with water resulted in a significant improvement in consciousness and orientation within one hour. In addition to recognizing the toxidrome, prompt and effective treatment for the intoxicated patient is essential. Given the prevalence of betel nut chewing in Taiwan, emergency physicians should be particularly vigilant of arecoline toxicity.
PubMed: 37089667
DOI: 10.6705/j.jacme.202303_13(1).0006 -
Journal of Oral and Maxillofacial... 2022The intestine plays an important role in the digestion and absorption of ingested food and the elimination of undigested food, microbes, and microbial products. The...
BACKGROUND
The intestine plays an important role in the digestion and absorption of ingested food and the elimination of undigested food, microbes, and microbial products. The functional reliability of the intestinal mucosal epithelial cells depends on the organised regulation of the epithelial cells, mucus layer, the intercellular tight junction, host innate and acquired immune response. The mucus layer of the gastrointestinal tract is the first line of innate host defense, essentially because of the secretory products of intestinal cells.
AIM
Present study was conducted to evaluate the effect of arecoline on the gastrointestinal system due to systemic absorption of the drug during the induction period of oral submucous fibrosis (OSMF) in Wistar rats.
METHODS
Oral submucous fibrosis was induced by submucosal injection of arecoline in the buccal mucosa. Arecoline hydrochloride at a dosage of 10 mg/kg was injected into the submucosa of right buccal mucosa in experimental animals over a period of 3 months on every alternate day. After which, right buccal mucosa, gastrointestinal tract organs like stomach, large intestine, small intestine and liver were dissected, subjected to histopathological evaluation of the healthy and experimental Wistar rats were subjected to histopathological evaluation.
RESULTS
On histological evaluation, OSMF was seen to affect Wistar rats showed significant changes in oral mucosa, decrease number of goblet cells in the small intestine as well in the large intestine and deranged hepatocytes. These marked changes indicated a definite effect on the gastro intestinal system by arecoline.
CONCLUSION
The study has highlighted the effect of arecoline due to systemic absorption during the induction process of OSMF in Wistar rats.
PubMed: 37082066
DOI: 10.4103/jomfp.jomfp_451_21 -
Frontiers in Pharmacology 2023Non-alcoholic fatty liver disease (NAFLD) has gradually become the primary cause of fatty liver disease. Betel nuts have been used to treat gastrointestinal diseases....
Non-alcoholic fatty liver disease (NAFLD) has gradually become the primary cause of fatty liver disease. Betel nuts have been used to treat gastrointestinal diseases. In the present study, we analyzed the pathology, serology, gut flora, and metabolites in a rat model of NAFLD, with and without betel nut alkaloid treatment, using an integrated approach involving pathology, serological testing, 16S rRNA gene sequencing, and ultra-performance liquid chromatography-mass spectrometry metabolomics. Two rats were used for model validation. Thirty SD rats were included and divided into the normal group (C group), NAFLD model group (M group), low-dose group, medium-dose group (T group), and high-dose group with intraperitoneal injection of arecoline. The expression of blood lipids was significantly downregulated at all three arecoline concentrations ( < 0.05). Alpha-diversity analysis of the intestinal flora showed significant differences among the three groups, with a significant reduction in population diversity in the M group and a recovery of population diversity after arecoline treatment. At the phylum level, the relative abundance of was significantly higher in the T group and in the M group. The KEGG metabolic pathways included polyketide sugar unit biosynthesis and hypertrophic cardiomyopathy. Thirty-three significantly different metabolites were identified among the groups. Significantly different metabolites between groups T and M included indolepyruvate, 2-deoxystreptamine, sakuranetin, glycyl-leucine, and riboflavin. The KEGG metabolic pathway suggested a potential role for arachidonic acid metabolism, serotonergic synapses, neuroactive ligand-receptor interactions, tyrosine metabolism, and regiomelanin. Vitamin digestion and absorption, as well as regulation of lipolysis in adipocytes, were the main metabolic pathways that distinguished the T vs. M groups. PGE2 is involved in several metabolic pathways. Correlation analysis showed that 29 bacterial species were significantly associated with PGE2 levels in the M and T groups. , , , unidentified , unidentified , and five other bacterial groups are unique in the PGE2 metabolic pathway regulated by arecoline. Arecoline has lipid-lowering effects and may exert therapeutic effects in NAFLD through intestinal metabolites and intestinal flora, as well as through the //-COX2/PGE2 pathway. Thus, arecoline may represent a potential drug or target for NAFLD treatment.
PubMed: 37050898
DOI: 10.3389/fphar.2023.1132026 -
International Journal of Molecular... Mar 2023Areca nut has been listed as one of the most addictive substances, along with tobacco, alcohol and caffeine. Areca nut contains seven psychoactive alkaloids; however,...
Areca nut has been listed as one of the most addictive substances, along with tobacco, alcohol and caffeine. Areca nut contains seven psychoactive alkaloids; however, the effects of these alkaloids on embryonic development and motor behavior are rarely addressed in zebrafish embryo-larvae. Herein, we investigated the effects of exposure to three alkaloids (arecoline and secondary metabolites-arecaidine and arecoline -oxide) on the developmental parameters, locomotive behavior, oxidative stress and transcriptome of zebrafish embryos. Zebrafish embryos exposed to different concentrations (0, 0.1, 1, 10, 100 and 1000 μM) of arecoline, arecaidine and arecoline -oxide showed no changes in mortality and hatchability rates, but the malformation rate of zebrafish larvae was significantly increased in a dose-dependent manner and accompanied by changes in body length. Moreover, the swimming activity of zebrafish larvae decreased, which may be due to the increase in reactive oxygen species and the imbalance between oxidation and antioxidation. Meanwhile, transcriptome analysis showed that endoplasmic reticulum stress and the apoptosis p53 signaling pathway were significantly enriched after exposure to arecoline and arecoline -oxide. However, arecaidine exposure focuses on protein synthesis and transport. These findings provide an important reference for risk assessment and early warning of areca nut alkaloid exposure.
Topics: Animals; Arecoline; Zebrafish; Alkaloids; Oxidative Stress; Endoplasmic Reticulum Stress; Areca
PubMed: 37047326
DOI: 10.3390/ijms24076327 -
Cells Mar 2023The areca nut is a high-risk carcinogen for head and neck cancer (HNC) patients in Southeast Asia. The underlying molecular mechanism of areca nut-induced HNC remains...
The areca nut is a high-risk carcinogen for head and neck cancer (HNC) patients in Southeast Asia. The underlying molecular mechanism of areca nut-induced HNC remains unclear, especially regarding the role of long non-coding RNA (lncRNA). This study employed a systemic strategy to identify lncRNA signatures related to areca nut-induced HNC. In total, 84 cancer-related lncRNAs were identified. Using a PCR array method, 28 lncRNAs were identified as being dysregulated in HNC cells treated with areca nut (17 upregulated and 11 downregulated). Using bioinformatics analysis of The Cancer Genome Atlas Head-Neck Squamous Cell Carcinoma (TCGA-HNSC) dataset, 45 lncRNAs were differentially expressed in tumor tissues from HNC patients (39 over- and 6 under-expressions). The integrated evaluation showed 10 lncRNAs dysregulated by the areca nut and altered expression in patients, suggesting that these panel molecules participate in areca nut-induced HNC. Five oncogenic (LUCAT1, MIR31HG, UCA1, HIF1A-AS2, and SUMO1P3) and tumor-suppressive (LINC00312) lncRNAs were independently validated, and three key molecules were further examined. Pathway prediction revealed that LUCAT1, UCA1, and MIR31HG modulate multiple oncogenic mechanisms, including stress response and cellular motility. Clinical assessment showed that these lncRNAs exhibited biomarker potentials in diagnosis (area under the curve = 0.815 for LUCAT1) and a worse prognosis (both < 0.05, survival analysis). Cellular studies further demonstrated that MIR31HG facilitates areca nut-induced cancer progression, as silencing this molecule attenuated arecoline-induced invasion ability in HNC cells. This study identified lncRNA signatures that play a role in areca nut-induced HNC. These molecules may be further applied in risk assessment, diagnosis, prognosis, and therapeutics for areca nut-associated malignancies.
Topics: Humans; RNA, Long Noncoding; Areca; Nuts; Head and Neck Neoplasms; Squamous Cell Carcinoma of Head and Neck
PubMed: 36980216
DOI: 10.3390/cells12060873